Is Hyperthermic Intraperitoneal Chemotherapy Appropriate for Colon Cancer?

Colorectal cancer (CRC) with peritoneal metastases is a complex disease and its management presents significant clinical challenges. In well-selected patients at experienced centers, CRS/hyperthermic intraperitoneal chemotherapy (HIPEC) can be performed with acceptable morbidity and is associated with prolonged survival. Based on the results of recent randomized controlled trials, HIPEC using oxaliplatin after CRS with shortened perfusion periods (30 minutes) is no longer recommended. There is a movement toward utilizing mitomycin C as a first-line intraperitoneal agent with extended perfusion times (90-120 minutes); however, there is currently little prospective evidence to support its widespread use.

Gut Roseburia is a protective marker for peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC), particularly for advanced stage of GC, commonly undergoes peritoneal metastasis (PM), which is the leading cause of GC-related death. However, there currently has no reliable biomarker to predict the onset of GCPM. It is well known that the imbalance of gut microbiota contributes to the development and metastasis of gastrointestinal tumors. Unfortunately, little is known about how the alternation in gut microbiota is associated with the onset of GCPM. METHODS: Our current study analyzed structural characteristics and functional prediction of gut microbiota in GC patients with PM (PM group) and without PM (non-PM group). Fresh fecal samples were collected from a discovery cohort (PM = 38, non-PM = 54) and a validation cohort (PM = 15, non-PM = 21) of GC patients and their 16S ribosomal RNA (16s rRNA) gene amplicons were sequenced, followed by bioinformatics. RESULTS: The results indicated an increase in the biodiversity of gut microbiota in the non-PM group of the discovery cohort, compared with the PM group. Moreover, LEfSe analysis found 31 significantly different microorganisms, of which the Roseburia ranked the fifth in the random forest (RF) model. The characteristics of intestinal microbiota in GCPM patients were changed, and the abundance of Roseburia in gut microbiota from the GCPM patients was reduced and receiver operating characteristic (ROC) analysis revealed that the reduced abundance of gut Roseburia effectively predicted the onset of GCPM. CONCLUSION: This signature was also observed in the validation cohort. Therefore, Roseburia is a protective microbial marker and the reduced abundance of Roseburia in gut microbiota may help early diagnosis of GCPM.

Novel nomogram and risk stratification for peritoneal recurrence after curative resection in gastric cancer.

Peritoneal recurrence (PR) in gastric cancer after curative resection has poor prognosis. Therefore, we aimed to construct a nomogram to predict PR, and establish PR score for risk stratification to guide adjuvant chemotherapy. A total of 315 patients with gastric cancer after radical surgery were included, and randomly stratified into training group (n = 221) and validation group (n = 94). Univariate and multivariate analyses were used to determine predictive factors of PR. The nomogram was constructed to predict the risk of PR. We utilized the time-dependent area under the receiver operating characteristic (ROC) curves (AUCs), calibration curves, and decision curve analysis (DCA) to evaluate the performance of the nomogram. Multivariate analysis showed that tumor site, N stage, preoperative CEA, and postoperative CA199 were independent predictors of PR. A nomogram was constructed to predict PR based on these factors. The AUC value was 0.755 in the training group and 0.715 in the validation group. The calibration curves showed good agreement between prediction and observation in the training and validation groups. The decision curve analysis displayed a good net benefit of the nomogram. The novel PR score was developed and patients were stratified into the low-, medium-, and high -risk groups. For the high-risk group, postoperative adjuvant chemotherapy significantly improved patients' overall survival (OS) and disease-free survival (DFS). The establishment of nomogram facilitates the prediction of PR after radical gastrectomy, and a novel PR score may help guide adjuvant chemotherapy for gastric cancer.

Comparative assessment of the capability of machine learning-based radiomic models for predicting omental metastasis in locally advanced gastric cancer.

The study aims to investigate the predictive capability of machine learning algorithms for omental metastasis in locally advanced gastric cancer (LAGC) and to compare the performance metrics of various machine learning predictive models. A retrospective collection of 478 pathologically confirmed LAGC patients was undertaken, encompassing both clinical features and arterial phase computed tomography images. Radiomic features were extracted using 3D Slicer software. Clinical and radiomic features were further filtered through lasso regression. Selected clinical and radiomic features were used to construct omental metastasis predictive models using support vector machine (SVM), decision tree (DT), random forest (RF), K-nearest neighbors (KNN), and logistic regression (LR). The models' performance metrics included accuracy, area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In the training cohort, the RF predictive model surpassed LR, SVM, DT, and KNN in terms of accuracy, AUC, sensitivity, specificity, PPV, and NPV. Compared to the other four predictive models, the RF model significantly improved PPV. In the test cohort, all five machine learning predictive models exhibited lower PPVs. The DT model demonstrated the most significant variation in performance metrics relative to the other models, with a sensitivity of 0.231 and specificity of 0.990. The LR-based predictive model had the lowest PPV at 0.210, compared to the other four models. In the external validation cohort, the performance metrics of the predictive models were generally consistent with those in the test cohort. The LR-based model for predicting omental metastasis exhibited a lower PPV. Among the machine learning algorithms, the RF predictive model demonstrated higher accuracy and improved PPV relative to LR, SVM, KNN, and DT models.

Survival Difference of Endometrial Cancer Patients with Peritoneal Metastasis Receiving Cytoreductive Surgery (CRS) with and without Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Systematic Review and Meta-Analysis.

Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected additional survival benefits of CRS plus HIPEC over CRS only. Twenty-one and ten studies with a total number of 1116 and 152 cases investigating CRS only and CRS plus HIPEC were identified, respectively. When all articles were analyzed, the 1-year survival rate was 17.60% higher for CRS plus HIPEC (82.28% vs. 64.68%; p = 0.0102). The same tendency was observed for the 2-year (56.07% vs. 36.95%; difference: 19.12%; p = 0.0014), but not for the 5-year (21.88% vs. 16.45%; difference: 5.43%; p = 0.3918) survival rates. The same clinical significance, but statistically less strong observations, could be made if only the studies published after 2010 were investigated (1-year survival rate: 12.08% and p = 0.0648; 2-year survival rate: 10.90% and p = 0.0988). CRS remains one of the core elements of ECPM treatment, but the addition of HIPEC to CRS can increase the positive clinical outcome, especially in the first 2 years.

[A Case of Perforated Low-Grade Appendiceal Mucinous Neoplasm Diagnosed During Appendectomy].

A 46-year-old female presented persistent right lower abdominal pain for 4 days. Computed tomography revealed an enlarged appendix with a surrounding low-attenuation mass. The patient was diagnosed with appendiceal abscess-forming appendicitis and initially treated with antibiotics. However, owing to the manifestation of nausea as a side effect, laparoscopic appendectomy was performed 3 days after the initial consultation. Intraoperative examination revealed mucinous material on the surface of the appendix and within the abdominal cavity, leading to the decision to perform an appendectomy with partial cecum resection and excision of the omentum with mucinous deposits. Pathological examination confirmed the diagnosis of a perforating low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei. The patient was subsequently referred to a specialized center for ongoing management, and at 9 months postoperatively, surveillance is being conducted. Low-grade appendiceal mucinous neoplasms can progress to pseudomyxoma peritonei through perforation; however, an optimal treatment approach has not yet been established. In particular, patients in advanced stages of the disease often require challenging management decisions. This case is reported along with a review of the literature to provide further guidance.

LAMN port-site metastasis after laparoscopic oophorectomy for a presumed ovarian tumour treated with CRS and HIPEC.

Low-grade appendiceal mucinous neoplasm (LAMN) may culminate as a mucin-secreting disease known as pseudomyxoma peritonei (PMP). Once the diagnosis of LAMN and PMP is made, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC) are indicated.Herein, we present a female patient in her 50s who was diagnosed with an ovarian mass for which she underwent laparoscopic oophorectomy. As the pathology of the ovary showed a tumour of gastrointestinal origin, she then underwent CRS and HIPEC with a final pathology of LAMN. Six weeks later, a mucinous lesion confined to the abdominal wall was detected on a postoperative CT. Suspected for port-site metastasis at the laparoscopic trocar site, we treated this lesion using the same principles of treatment as the intra-abdominal disease. The abdominal wall mass was surgically resected, and the cavity created was irrigated with mitomycin C. On 30 months of follow-up, the patient had no evidence of disease.

T-cell responses in colorectal peritoneal metastases are recapitulated in a humanized immune system mouse model.

Background: The occurrence of peritoneal metastasis (PM) in patients with colorectal cancer (CRC) has a dismal prognosis. There is often limited response to systemic- and immunotherapy, even in microsatellite unstable (MSI) CRC. To overcome therapy resistance, it is critical to understand local immune environment in the peritoneal cavity, and to develop models to study anti-tumor immune responses. Here, we defined the peritoneal immune system (PerIS) in PM-CRC patients and evaluate the pre-clinical potential of a humanized immune system (HIS) mouse model for PM-CRC. Methods: We studied the human PerIS in PM-CRC patients (n=20; MSS 19/20; 95%) and in healthy controls (n=3). HIS mice (NODscid gamma background; n=18) were generated, followed by intraperitoneal injection of either saline (HIS control; n=3) or human MSS/MSI CRC cell lines HUTU80, MDST8 and HCT116 (HIS-PM, n=15). Immune cells in peritoneal fluid and peritoneal tumors were analyzed using cytometry by time of flight (CyTOF). Results: The human and HIS mouse homeostatic PerIS was equally populated by NK cells and CD4+- and CD8+ T cells, however differences were observed in macrophage and B cell abundance. In HIS mice, successful peritoneal engraftment of both MSI and MSS tumors was observed (15/15; 100%). Both in human PM-CRC and in the HIS mouse PM-CRC model, we observed that MSS PM-CRC triggered a CD4+ Treg response in the PerIS, while MSI PM-CRC drives CD8+ TEMs responses. Conclusion: In conclusion, T cell responses in PM-CRC in HIS mice mirror those in human PM-CRC, making this model suitable to study antitumor T cell responses in PM-CRC.

Phase I/II Clinical Study of PRaG Regimen Combined With Intraperitoneal Infusion of PD-1 Inhibitor for Advanced Refractory Solid Tumors With Cancerous Ascites (PRaG4.0P Study).

Objective: The prognosis of malignant tumors with peritoneal metastases and cancerous ascites has generally been poor, with limited treatment options. The PRaG regimen, which comprised of hypofractionated radiotherapy, programmed cell death-1 (PD-1) inhibitor, and granulocyte-macrophage colony-stimulating factor (GM-CSF), showed a survival advantage in patients with advanced solid tumors who failed at least the first line of standard systemic treatment. Intraperitoneal infusion of PD-1 inhibitors may be a novel therapeutic strategy for managing malignant ascites. Integrating the PRaG regimen with intraperitoneal perfusion of a PD-1 inhibitor might control malignant ascites and provide further survival benefits in these patients. This proposed study aims to investigate the safety and efficacy of intraperitoneal infusion of serplulimab in combination with the PRaG regimen in patients with simultaneous advanced solid tumors and cancerous ascites who fail at least the first-line treatment. Methods: This proposed study is a prospective, single-arm, open-label, multicenter clinical trial. All eligible patients will receive 2 cycles of intensive treatment, a combination of PRaG regimen with an intraperitoneal infusion of PD-1 inhibitor. The patients who are beneficially treated with intensive treatment will receive consolidation treatment every 2 weeks until ascites disappear, disease progression occurs, intolerable toxicity occurs, or for up to 1 year. Phase I of this study will be conducted using a modified 3 + 3 design. The dose of intraperitoneal infusion of PD-1 inhibitor for phase II will be determined according to dose-limiting toxicity evaluation in the phase I study. Conclusion: This prospective, open-label, multicenter study will potentially lead to intraperitoneal perfusion of a PD-1 inhibitor being a new strategy for malignant ascites patients and provide a meaningful efficacy and safety of the combination of PRaG regimen with an intraperitoneal infusion of PD-1 inhibitor for these patients.

Long-Term Outcomes following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Origin.

BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a major treatment of colorectal peritoneal carcinomatosis (CPC). The aim was to determine the disease-free survival (DFS) and overall survival (OS) of patients undergoing CRS-HIPEC for CPC and factors associated with long-term survival (LTS). METHODS: consecutive CPC patients who underwent CRS-HIPEC at a HIPEC center between 2007 and 2021 were included. Actual survival was calculated, and Cox proportional hazards models were used to identify factors associated with OS, DFS and LTS. RESULTS: there were 125 patients with CPC who underwent primary CRS-HIPEC, with mean age of 54.5 years. Median follow-up was 31 months. Average intraoperative PCI was 11, and complete cytoreduction (CC-0) was achieved in 96.8%. Median OS was 41.6 months (6-196). The 2-year and 5-year OS were 68% and 24.8%, respectively, and the 2-year DFS was 28.8%. Factors associated with worse OS included pre-HIPEC systemic therapy, synchronous extraperitoneal metastasis, and PCI ≥ 20 (p < 0.05). Progression prior to CRS-HIPEC was associated with worse DFS (p < 0.05). Lower PCI, fewer complications, lower recurrence and longer DFS were associated with LTS (p < 0.05). CONCLUSION: CRS and HIPEC improve OS in CPC patients but they have high disease recurrence. Outcomes depend on preoperative therapy response, extraperitoneal metastasis, and peritoneal disease burden.

Incidental Diagnosis of Malignant Peritoneal Mesothelioma During Liver Transplantation Surgery: A Case Report.

BACKGROUND Malignant peritoneal mesothelioma (MPM) is a rare, lethal tumor of serous membranes. The most common factor reported in association with MPM is asbestos exposure, while viral infections, genetic predisposition, paraneoplastic syndrome, and altered immunity have been described as well. The diagnosis can be challenging among those with lower tumor burden as well as nonspecific symptoms, and it is not unusual to discover the diagnosis incidentally. CASE REPORT A middle-aged woman with decompensated cirrhosis underwent extensive pre-transplant workup, showing no evidence of malignancy. She had a personal history of asbestos exposure and family history of MPM in the extended family. During transplant surgery, a few peritoneal nodules were noted, leading to termination of the procedure. Pathological analysis confirmed malignant MPM. A multidisciplinary discussion led to following a conservative treatment approach without any intervention, due to higher risk of worsening hepatic decompensation associated with peritonectomy and intraperitoneal chemotherapy. The patient's hepatic decompensation resolved 6 months after the aborted liver transplant operation. Since the diagnosis of MPM, positron emission tomography scans have shown no recurrence of MPM for 3 consecutive years. CONCLUSIONS This is the first case of MPM diagnosed incidentally during a liver transplantation surgery. This case highlights the challenges in the diagnosis and management of MPM in a patient with decompensated liver disease. A multidisciplinary approach and following a consensus decision led to prolonged survival in the described patient.

Targeting vascular disrupting agent-treated tumor microenvironment with tissue-penetrating nanotherapy.

Cancer treatment with vascular disrupting agents (VDAs) causes rapid and extensive necrosis in solid tumors. However, these agents fall short in eliminating all malignant cells, ultimately leading to tumor regrowth. Here, we investigated whether the molecular changes in the tumor microenvironment induced by VDA treatment sensitize the tumors for secondary nanotherapy enhanced by clinical-stage tumor penetrating peptide iRGD. Treatment of peritoneal carcinomatosis (PC) and breast cancer mice with VDA combretastatin A-4 phosphate (CA4P) resulted in upregulation of the iRGD receptors αv-integrins and NRP-1, particularly in the peripheral tumor tissue. In PC mice treated with CA4P, coadministration of iRGD resulted in an approximately threefold increase in tumor accumulation and a more homogenous distribution of intraperitoneally administered nanoparticles. Notably, treatment with a combination of CA4P, iRGD, and polymersomes loaded with a novel anthracycline Utorubicin (UTO-PS) resulted in a significant decrease in the overall tumor burden in PC-bearing mice, while avoiding overt toxicities. Our results indicate that VDA-treated tumors can be targeted therapeutically using iRGD-potentiated nanotherapy and warrant further studies on the sequential targeting of VDA-induced molecular signatures.

The immunomodulatory role of paracrine signalling factor VSIG4 in peritoneal metastases.

Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.

Reliability, diagnostic value, and diagnostic yield of ultrasound-guided percutaneous core needle biopsy for peritoneal lesions.

INTRODUCTION: Peritoneal lesions cannot be definitively distinguished based on clinical and imaging characteristics alone. This study aimed to evaluate the reliability, diagnostic value, and diagnostic yield of ultrasound-guided percutaneous core needle biopsy (PCNB) for peritoneal lesions. METHODS: A retrospective analysis of 129 patients who underwent PCNB for peritoneal lesions was performed to assessed technical completion and diagnostic yield. RESULTS: The results showed that ultrasound-guided PCNB is a safe and reliable diagnostic tool with high diagnostic yield for peritoneal lesions. Technical feasibility and diagnostic yield rates were 100% and 89.9%, respectively. The diagnostic yield was lower for patients with a known history of cancer and a short anteroposterior diameter of the target lesion. CONCLUSIONS: These findings suggest that ultrasound-guided PCNB could be considered as a first-line diagnostic tool for peritoneal lesions, as it offers a minimally invasive and accurate means of obtaining tissue samples for diagnosis.

Injectable Nanocomposite Hydrogels Improve Intraperitoneal Co-delivery of Chemotherapeutics and Immune Checkpoint Inhibitors for Enhanced Peritoneal Metastasis Therapy.

Intraperitoneal co-delivery of chemotherapeutic drugs (CDs) and immune checkpoint inhibitors (ICIs) brings hope to improve treatment outcomes in patients with peritoneal metastasis from ovarian cancer (OC). However, current intraperitoneal drug delivery systems face issues such as rapid drug clearance from lymphatic drainage, heterogeneous drug distribution, and uncontrolled release of therapeutic agents into the peritoneal cavity. Herein, we developed an injectable nanohydrogel by combining carboxymethyl chitosan (CMCS) with bioadhesive nanoparticles (BNPs) based on polylactic acid-hyperbranched polyglycerol. This system enables the codelivery of CD and ICI into the intraperitoneal space to extend drug retention. The nanohydrogel is formed by cross-linking of aldehyde groups on BNPs with amine groups on CMCS via reversible Schiff base bonds, with CD and ICI loaded separately into BNPs and CMCS network. BNP/CMCS nanohydrogel maintained the activity of the biomolecules and released drugs in a sustained manner over a 7 day period. The adhesive property, through the formation of Schiff bases with peritoneal tissues, confers BNPs with an extended residence time in the peritoneal cavity after being released from the nanohydrogel. In a mouse model, BNP/CMCS nanohydrogel loaded with paclitaxel (PTX) and anti-PD-1 antibodies (αPD-1) significantly suppressed peritoneal metastasis of OC compared to all other tested groups. In addition, no systemic toxicity of nanohydrogel-loaded PTX and αPD-1 was observed during the treatment, which supports potential translational applications of this delivery system.